Bone marrow derived cells (BMDC) have significant plasticity allowing them to give rise to various nonhematopoietic cell types including epithelial cells of the lung, liver, gastrointestinal tract, and skin. These findings present tremendous possibilities for the use of cell therapy to treat tissue injury and disease. They suggest that BMDC may represent a renewable pool of epithelial precursors, and thus open new avenues for the development of treatment for currently intractable disorders. There is considerable controversy regarding the extent to which the BM to epithelial transition occurs, and whether it is due to cell:cell fusion verses cell differentiation. We hypothesize that the engraftment of BMDC as mature epithelial cells in the GI tract occurs by both fusion of hematopoietic cells mature epithelial cells and by differentiation of nonhematopoietic BM derived precursors. Corollaries to this hypothesis would be that the BM contains different populations that are capable of engraftment into epithelial cells, and that different types of tissue injury could promote engraftment of marrow derived epithelial cells via different mechanisms. In preliminary data, we have demonstrated that BMDC can become functional epithelial cells in the GI tract. Specifically, we have used mice lacking the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) as a model system for assessing engraftment of functional epithelial cells in the GI tract. Using this model, we will test the hypotheses that HSC and cells derived therefrom become epithelial cells only through fusion, and that nonhematopoietic mesenchymal stem cells (MSC) can differentiate into GI epithelial cells without fusion. Engraftment of BMDC as functional epithelial cells could facilitate healing in response to tissue injury. The data obtained will lead us to design novel therapeutic strategies tissue injury and disease. [unreadable] [unreadable] [unreadable]